In the proposed study we will examine how illicit stimulant use affects the longitudinal course of neurocognitive functioning in individuals infected with human immunodeficiency virus (HIV), and how host-genetic variation modulates this. While it is has been established that both HIV infection and stimulant use result in neurocognitive impairment, and that these effects are additive or even synergistic, the interactive relationship between these two factors as it evolves over time has not yet been examined. Further, while the role of host- genetics in the progression of HIV/AIDS has received growing attention during the past few years, its contribution to the progression and characteristics of neurocognitive deficits over time remains to be determined. To address this, we will employ two genetic association methods. First, we will utilize a candidate gene approach with a large sample (N = 1000) of HIV+ and HIV- individuals that will focus on polymorphisms that affect the metabolism and activity of dopamine (DA). This neurotransmitter is implicated in the neuropathogenesis of HIV- associated neurocognitive disorders (HAND) and cognitive sequelae of chronic stimulant abuse. Further, research has shown that functional polymorphisms in DA-related genes can affect neuropsychological functioning via alterations in underlying neurophysiology, and that this occurs in brain regions similar to those affected in neuroAIDS. Therefore, examination of DA-related polymorphisms may add a critical tier of knowledge for explaining inter-individual variation in neuropsychological outcomes and progression among HIV+ drug users. In this exploratory study, we will also examine variants of other genes associated with neurobiological and immune functioning, including ApoE, brain-derived neurotrophic factor, and tumor necrosis factor-alpha. In the second approach, we will examine existing data from a genome-wide association (GWA) scan of 496 HIV+ individuals. We will be able to examine over 555,000 single nucleotide polymorphisms (SNPs) in an effort to detect novel genes associated with neurocognitive phenotypes, such as progression and diagnosis of HAND. Such a large scale genetic analysis of HAND neuropathogenesis has yet to be conducted. The proposed study will use the Multicenter AIDS Cohort Study (MACS), a longitudinal study of the natural history and clinical outcomes in HIV+ individuals. Neuropsychological, psychiatric, and virologic data on cohort of largely Caucasian, gay males are collected at regular intervals. Data exist for both HIV+ and HIV- individuals, as well as individuals with varying stimulant use patterns. Fluids are available for DNA extraction and genotyping. The proposed research team consists of experts in psychiatric genetics, neuropsychology, NeuroAIDS, and statistics with proven ability by successfully carrying out similar studies and to work with MACS data. The results of these investigations will lead to greater understanding of the neuropathogenesis of HAND, identification of pharmaceutical targets, and ultimately greater quality of life for those infected with HIV. The results of these investigations will be immediately translatable to public health efforts. Specifically, they will further illuminate understanding of the neuropathogenesis of HAND. Further, the identification of host- genetic factors in the neuropathogenesis of HAND will enable development of specific pharmaceutical treatments, ultimately leading to greater quality of life for those infected with HIV.